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  • Open Access

Cish actively silences tcr signaling in CD8+ T cells to maintain tumor tolerance

  • 1,
  • 2,
  • 2,
  • 2,
  • 3,
  • 3,
  • 1,
  • 3,
  • 2,
  • 3,
  • 2 and
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Journal for ImmunoTherapy of Cancer20153(Suppl 2):P39

https://doi.org/10.1186/2051-1426-3-S2-P39

Published: 4 November 2015

Keywords

  • Tumor Microenvironment
  • Tumor Regression
  • Durable Regression
  • Proteasomal Degradation
  • Cancer Immunotherapy

Background

Improving the functional avidity of effector T cells is critical in overcoming inhibitory factors within the tumor microenvironment and eliciting tumor regression.

Methods

We have found that Cish, a member of the Suppressor of Cytokine Signaling (SOCS) family, is induced by TCR stimulation in CD8+ T cells and inhibits their functional avidity against tumor.

Results

Genetic deletion of Cish in CD8+ T cells enhances their expansion, functional avidity and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors. Although Cish is commonly thought to block STAT5 activation, we found that the primary molecular basis of Cish suppression is through inhibition of TCR signaling. Cish physically interacts with the TCR intermediate PLCg1, targeting it for proteasomal degradation following TCR stimulation. Furthermore we extend these findings to patients PBL retrovirally transduced with tumor-specific TCRs and shorthairpin microRNAs targeting CISH.

Conclusions

These findings establish a novel targetable interaction that regulates the functional avidity of tumor-specific CD8+ T cells and can be manipulated to improve adoptive cancer immunotherapy.

Authors’ Affiliations

(1)
NIH/NCI - Surgery Branch, Bethesda, USA
(2)
NCI, Bethesda, USA
(3)
Center for Cancer Research, NCI/NIH, Bethesda, USA

Copyright

© Palmer et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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